Basic esters of polyarylacetic acids and process of making the same



Patented May 11, 1937 PATENT orrlc BASIC ESTERS F POLYARYLACETIG ACIDSANI) PROCESS OF MAKING THE SAME 1 Karl Miescher, Itiehen, near Basel,and Karl Hoifmann, Basel, Switzerland, assignors to the firm of Societyof Chemical Industry in Basic,

Basel, Switzerland No Drawing. Application July 6, 1935, Serial No.

30,166. In Switzerland July 12, 1934 16 Claims. (01 260-43) It is knownthat many basic esters of tropic acid have an action similar to that ofatropin, although weaker. Basic esters-of certain other organic acidsalso exhibit activity, for instance such 5 esters of mandelic'acid,atrolactic acid, atroglyceric acid, benzoic acid and orthoandmetaoxybenzoic acid. Quite special in this respect is benzilicacid-2,2-dimethyl-S-diethyl-aminopropanol ester; its extraordinary toxiccharacter forbids its use in the clinic (see K. Fromherz, Archiv fiirexperimentelle Pathologie und Pharmakologie, 173 (1933) page 116).

This invention relates to the manufacture oi basic esters ofpolyarylacetic acids, which are compounds of considerably greatercompatibility than the said ester of benzilic acid. Thus, for example,the easily accessible dialkylaminoethanol ester of diphenylacetic acidhas an extraordinarily powerful effect on the unstriated mus- 2g cles..This is unexpected, since hitherto it has been supposed that thepresence of an aliphatic hydroxyl group in the acid residue (tropicacid, atrolaotic acid, atroglyceric acid, mandelic acid or benzilicacid) favored the action. The new compounds may be made by acting uponpolyarylacetic acids or on a halide, ester or anhydride thereof, in thepresence or absence of a condensing agent, with an aminoalkanol disubstituted at the nitrogen atom, or by the action of a reactive ester ofan aminoalkanol, disubstituted at the nitrogen, on a polyarylacetic acidor a salt thereof, if desired in the presence of an agent which bindsacid. Alternatively, polyarylacetic acids may be converted into theirhalogen- 36 alkanol esters and the latter caused to react with asecondary amine.

For the production of the halogen alkanol esters the operation ispreferably conducted in such a manner that alkylene-halogen-hydrines 40are caused to react on polyarylacetic acids or the halides, esters oranhydrides thereof, in the presence or absence of condensing agents, orthat. al-

- kylene-halogen-hydrines or alkylene-dihalides are caused to react onsalts of polyarylacetic acids,

hydroxyl-group which may be present by halogen. By the addition of analkyl halide, an alkylene halide, an aryl sulfonic acid ester, a.dialkylsulfate, 0 an arylalkyl halide or the like, quaternary ammoniumcompounds of the bases in question can be produced.

Among reactive esters of aminoalkanols are particularly included estersof these with hydrohalogen acids or arylsulfonic acids or the like.

and replacing in the compounds so obtained any,

The new compounds are useful for therapeutic application.

The following examples illustrate the'invention, the parts being byweight:

Example .1

10.6 are of a,a-diphenylacetic acid are treated with thionyl' chlorideand the diphenylacetyl chloride thusproduced is caused to react with 5}parts of diethylaminoethanol at C. The unadiphenylacetic acid 2(diethylamino) -ethauolesterhydrochloride of the formula CaHu V /CSEBerr-comom-cm-u thus produced is recrystallized from ethyl ace- Example 242.4 parts of diphenylacetic acid, 41 parts ofchlorethyl-diethylamine-hydrochloride, 55 parts of potassium carbonateand 120 parts of acetone are together heated to boiling in a refluxapparatus until the reaction is complete. After cooling, the whole isfiltered, the solid matter is washed with acetone and the filtrateandthe washings are evaporated to dryness, the residue being extracted withether. The etheral solution is washed with dilute sodium carbonatesolution and dried over potassium carbonate The oil left on evaporatingthe ether is fractionated in a high vacuum.- The base thus obtained isidentical with that described in Example 1.

The same compound may also be obtained by causing equivalent quantitiesof diphenylacetic acid ethylmethylor another ester to react withdiethylaminoethanol in the heat, and'fractionating the reaction productin a vacuum.

' Example 3 11.5 parts of'diphenylacetic acid chloride-are caused toreact, in presence ot- 30 parts of dry'pyridine, with 6.5 parts ofallylethvlaminoethanol of the formula (boiling at 172 C. at 740mm.pressure, obtained from allylbromide' and ethylaminoethanol) The productof the reaction is extracted with ether ethanol; the reaction mass isextracted with ether,

and the ethereal solution is washed with sodium carbonate solution anddried over potassium carbonate. The solvent is then eliminated and theoil thus obtained is fractionated in a high vacuum. The diphenylaceticacid-,2-allylethylaminoethanol ester of the formula Ewample 4 30 partsof triphenylacetic acid chloride are caused to react with 24 parts ofdiethylam-inocal-0H1 the ethereal solution washed with dilute sodiumcarbonate solution and dried over potassium carbonate.- Afterevaporation of the solvent the triphenylaceticacid-2-diethylaminoethanol ester of the formula obtained fat 160-170 c.at 0.07 mm. pressure,vmelts at B5-90 C., and forms a hydrochloride ofmelting point 164-167- C., amethyliodide of melting point 223-225 C.,and a methylchloride of melting point 198499 0.

Example 5 23 parts of diphenylacetic acidchlorlde .are caused toreactwith 8 parts of ethylenechlorohydrine in presence of pyridine. Thereaction product is shaken with ether and water; the ethereal solutionis dried, the solvent evaporated and the residue fractionated in avacuum. The

diphenylacetic acid-Z-chloro-ethanol ester of the formula CIHIoH-co'o-cm-cn,-ci

I CaHl v thus obtained boils at 130-435" 0. it-0.01 mm.

pressure. 2'1 parts of this compound are caused to react in the heatwith 14 parts of diethylamine; the reaction productis shaken with etherand water; the ethereal solution'is dried and the solvent evaporated.The diphenylacetic acid-2-diethylaminoethanol ester thus obtained isidentical with the substance described in Example 1 and2.

Instead of ethylene chlorhydrine -also other ethylene halogen-hydrines,for example ethylenebromohydrinamay be used.

In order to obtain the halogen-ethanol esterv used as intermediateproduct one can'also proacraoca.

is distilled in a high vacuum. It boils c'eed in the followlngmanner: analkali: salt of the diphenylacetic acid is caused to react with anethylenedihalide as, for instance, ethylene chlorobromide, ethylenebromide or ethylene iodide, or an ethylene halogen-hydrine is caused toreact thereupon, and the hydroxyethanol ester thus obtained is treated,for instance, with thlonyl chloride. 1 g

In similar manner the following compounds may be obtained:diphenylacetic acid-2-methylethylaminoethanol'ester (a colorless oil ofboiling point 136-138? C. at 0.015 mm. pressure) diphenylacetic acid- 2di-n-butylaminoethanol ester (boiling point 163-l65 C. at 0.01 mm.pressure, sulfate melting point 139-140 C.) diphenylacetic acid-2- point149-151 C.), diphenylacetic acid-meta-dimethyl aminocyclohexanol ester(viscous oils of boiling point PTO-180 C. at 0.035 mm. pressure); theorthoand para-compounds are also forming viscous oils. a

The parent materials hitherto not known for the production of the abovecompounds are ob tained as follows: methylethylaminoethanol (boilingpoint 146-148 C. at 734 mm. pressure) from ethylaminoethanol andformaldehyde in presence of formic acid; m-dimethyl aminocyclohexanol(boiling point 101-104 C. at 6 mm. pressure) by methylatingm-aminocyclohexanol of melting point 73 C., the latter being obtained byreducing m-acetylaminophenol with a catalyst and by subsequentsaponification. The orthoor para-compounds are obtained in an analogousmanner. I

What we claim is:-'

1. The basic esters of the formula .piperidinoethanol ester(hydrochloride melting wherein Y represents a member of the group conanunsubstituted alkylene chain .and a cyclohexane ring,whichsubstances'are soluble in organic solvents and insoluble in water,forming with acids water-soluble salts of strong antispasmodic action.2. The basic esters of the formula wherein 3 represents a member of thegroup consisting of a dialkylamine, an alkyl-allylamine and api'peridine ring, and R represents a member of the group consisting ofhydrogen and phenyl,

which substances are soluble in organic solvents and insoluble in water,forming with acids watersoluble salts of strong antispasmodic action. 3.The basic esters of the formula wherein 3; represents a member of thegroup consisting of a dialkylamine, an alkyl-allylamine and a piperidinering, which substances are soluble in organic solvents and insoluble inwater, forming with acids water-soluble salts of strong antispasmodicaction.

4. The basic ester of the formula which substance is a colorless oilsoluble in organic solvents and insoluble in water, forming with acidswater-soluble salts of strong antispasmodic action. i I 5. The basicester of the formula Ccfls CHr-CE:

wherein A stones for o cyclohexane whic I substances are soluble inorganic solvents and in- I soluble in water, forming with acidswater-soluble soils of strong entispesmodic action. 7 8. The basic %terof the formula w s CaHu I )QHiPGHi I CH-CQO-OH /CH$ I 00E; Clio-CH C or;i Ha which substance is a colorless oil soiubie in or-.

' genie solvents and insoluble in water, long 59 with coins wetersoiuble salts of strong antispss motile action," I

9. A process for the menufacture of hassle esters, I

I which comprises causing products of the formula to Q Co s 1 wherein R,represents at member of the group con 0 sisting of hydrogen and phenyland 3 represents s member of the group consisting of-omelkyl andhalogen, to react with products of the formuio wherein A represents, 2.member of the group con sisting of an nhstituted elisylene'cn and ncyclohexene ring, and :11 represents a member of the group consisting ofa diellcyiemine, memo eliylomine one, a piperldine ring. 10 A processfor the manufacture of basic W esters, which comprises causing productsof the formula \C-CO can formulo wherein R represents a member of thegroup consisting' of hydrogen and phenyl and a: represents a member ofthe group consisting of oxyalkyl and halogen, toreact with products ofthe formula HO-CHPCM wherein 11 represents a. member of the groupconsisting of a dialkylamine, an alkyl-allylaniine and a. piperidinering.

11. A process for the manufacture of basic 10 esters, which comprisescausing products of the formula.

Oc'tu GH-QOfi I 06m I 0 wherein 2 represents o mher of the gl'flupwusisting of owolml and halogen, to. react with products of the fomnuiaI wherein 1/ represents a member of the group consisting of adisihwismine, an nlkyl-allylnmine and a piper-mine ring.

' 12. A process for the nufacture of a. basic 5 esterpwhich consists incausing products of the formula k v t I CH-C C it,

wherein a; stands for a member selected from the group consisting ofonyaiky'l and halogen, to react with the product of the formula /CaHa Ias Ho-cHr-cm -N Cali's l3fA'process fortlse manufacture of a basicester, which consists in cousins products of the 40 Cum v CcHB I I Vwherein's stands for a member selected from the group consisting ofonyaiiryi and halogen, to react with the product of the formulas cur-on,

' cut-cu,

14. A process for the ufectnre of basic esters, whichconsists in cproducts of the formuls CuHa wherein .2: stands for s member selectedfrom the group consisting of oxyslkyl end halogen, to react withproducts of the formula wherein A stands for a, cyclohee ring and R1 andR2 stand for slksl.

1-5. A oroce forethe nufacture of basic esters, which cc" is in cogproducts of the for-mule out i cn-co-e I II .4 ao'zepaa wherein z standsfor'a member selected from the group consisting of oxyalkyl and halogen,to react with products of the formula r l o HOAN whez -ein A stands fora, cyclohexane ring.

whel em :1: stands fox: a. member selectea n'om the groilp consisting ofoxyalkyl and halogen, to react with a. product of the formula I ICHI-CH:

